Ternary low-temperature phototherapy nano-systems for the treatment of diabetic wounds.

The physicochemical environment at the sites of chronic diabetic wounds is an ideal habitat for bacteria, which exacerbate the deterioration of the microenvironment at the wound sites and consequently delay wound healing. In recent years, photothermal therapy has been considered an ideal non-antibiotic antimicrobial strategy. However, photothermal therapy alone is prone to cause damage to the body tissues. Herein, a (zeolitic imidazolate framework-8) ZIF-8/(mesoporous polydopamine) MPDA@(deoxyribonuclease I) DNase I ternary nanocomposite system was constructed, which exhibited good antimicrobial and antioxidant properties. Specifically, DNase I was first encapsulated into MPDA nanoparticles (NPs) and then coated with ZIF-8, which rapidly degrades in an acidic bacterial environment, triggering the release of antimicrobial Zn2+ and DNase I, thus enabling low-temperature (∼45 °C) PTT antimicrobial therapy. Meanwhile, the NPs can effectively regulate the oxidative stress environment at the trauma site because of the antioxidant effect of MPDA. Moreover, the experimental results of the diabetic wound infection mouse model showed that the prepared NPs could kill bacteria well and accelerate wound healing. Overall, the phototherapy strategy proposed in this study shows great potential in the treatment of chronically infected wounds.

Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer.

Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly ß-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.

All-in-One Engineering Multifunctional Nanoplatforms for Sensitizing Tumor Low-Temperature Photothermal Therapy In Vivo.

Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40-48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.

Allomelanin-based biomimetic nanotherapeutics for orthotopic glioblastoma targeted photothermal immunotherapy.

Immune checkpoint blockade (ICB) therapy has shown great potential in the treatment of malignant tumors, but its therapeutic effect on glioblastoma (GBM) is unsatisfactory because of the low immunogenicity and T cell infiltration, as well as the presence of blood-brain barrier (BBB) that blocks most of ICB agents to the GBM tissues. Herein, we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted photothermal therapy (PTT) and ICB synergistic therapy by loading immune checkpoint inhibitor CLP002 into the allomelanin nanoparticles (AMNPs) and followed by coating cancer cell membranes (CCM). The resulting AMNP@CLP@CCM can successfully cross the BBB and deliver CLP002 to GBM tissues due to the homing effect of CCM. As a natural photothermal conversion agent, AMNPs are used for tumor PTT. The increased local temperature by PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells. Importantly, PTT can effectively stimulate immunogenic cell death to induce tumor-associated antigen exposure and promote T lymphocyte infiltration, which can further amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Therefore, AMNP@CLP@CCM has great potential for the treatment of orthotopic GBM by PTT and ICB synergistic therapy. STATEMENT OF SIGNIFICANCE: The effect of ICB therapy on GBM is limited by the low immunogenicity and insufficient T-cell infiltration. Here we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted PTT and ICB synergistic therapy. In this nanoplatform, AMNPs are used as both photothermal conversion agents for PTT and nanocarriers for CLP002 delivery. PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells by increasing local temperature. Additionally, PTT also induces tumor-associated antigen exposure and promotes T lymphocyte infiltration to amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Thus, this nanoplatform holds great potential for orthotopic GBM treatment.

Manganese-Based Tumor Immunotherapy.

As an essential micronutrient, manganese (Mn) participates in various physiological processes and plays important roles in host immune system, hematopoiesis, endocrine function, and oxidative stress regulation. Mn-based nanoparticles are considered to be biocompatible and show versatile applications in nanomedicine, in particular utilized in tumor immunotherapy in the following ways: 1) acting as a biocompatible nanocarrier to deliver immunotherapeutic agents for tumor immunotherapy; 2) serving as an adjuvant to regulate tumor immune microenvironment and enhance immunotherapy; 3) activating host's immune system through the cGAS-STING pathway to trigger tumor immunotherapy; 4) real-time monitoring tumor immunotherapy effect by magnetic resonance imaging (MRI) since Mn2+ ions are ideal MRI contrast agent which can significantly enhance the T1 -weighted MRI signal after binding to proteins. This comprehensive review focuses on the most recent progress of Mn-based nanoplatforms in tumor immunotherapy. The characteristics of Mn are first discussed to guide the design of Mn-based multifunctional nanoplatforms. Then the biomedical applications of Mn-based nanoplatforms, including immunotherapy alone, immunotherapy-involved multimodal synergistic therapy, and imaging-guided immunotherapy are discussed in detail. Finally, the challenges and future developments of Mn-based tumor immunotherapy are highlighted.

Surface modification of titanium substrate via combining photothermal therapy and quorum-sensing-inhibition strategy for improving osseointegration and treating biofilm-associated bacterial infection.

Insufficient osseointegration and biofilm-associated bacterial infection are important challenges for clinical application of titanium (Ti)-based implants. Here, we constructed mesoporous polydopamine (MPDA) nanoparticles (NPs) loaded with luteolin (LUT, a quorum sensing inhibitor), which were further coated with the shell of calcium phosphate (CaP) to construct MPDA-LUT@CaP nanosystem. Then, MPDA-LUT@CaP NPs were immobilized on the surface of Ti implants. Under acidic environment of bacterial biofilm-infection, the CaP shell of MPDA-LUT@CaP NPs was rapidly degraded and released LUT, Ca2+ and PO4 3- from the surface of Ti implant. LUT could effectively inhibit and disperse biofilm. Furthermore, under near-infrared irradiation (NIR), the thermotherapy induced by the photothermal conversion effect of MPDA destroyed the integrity of the bacterial membrane, and synergistically led to protein leakage and a decrease in ATP levels. Combined with photothermal therapy (PTT) and quorum-sensing-inhibition strategy, the surface-functionalized Ti substrate had an antibacterial rate of over 95.59% against Staphylococcus aureus and the elimination rate of the formed biofilm was as high as 90.3%, so as to achieve low temperature and efficient treatment of bacterial biofilm infection. More importantly, the modified Ti implant accelerated the growth of cell and the healing process of bone tissue due to the released Ca2+ and PO4 3-. In summary, this work combined PTT with quorum-sensing-inhibition strategy provides a new idea for surface functionalization of implant for achieving effective antibacterial and osseointegration capabilities.

Fabrication of a pH-responsive core-shell nanosystem with a low-temperature photothermal therapy effect for treating bacterial biofilm infection.

Recently, photothermal therapy (PTT) has been recognized as a viable alternative strategy against bacterial biofilm infection. However, the hyperthermia required for PTT to ablate a biofilm usually induces damage in normal tissues/organs nearby. Herein, we developed zeolite-based imidazole framework (ZIF-8)-coated mesoporous polydopamine (MPDA) core-shell nanoparticles and then loaded Pifithrin-µ (PES), a natural inhibitor of heat-shock protein (HSP) that plays an essential role in bacteria resisting heating-induced damage. The ZIF-8 shell of the MPDA@ZIF-8/PES nanoplatform enabled a rapid degradation in response to the acidic environment in bacterial biofilm infection, which triggered the controlled release of PES and Zn ions. As a result, HSP was remarkably suppressed for enhancing PTT efficacy upon mild near-infrared light irradiation. In addition, the release of Zn2+ also had an antibacterial/antibiofilm effect. Thus, the fabricated nanosystem was able to induce the effective elimination of the bacterial biofilm, realizing low-temperature PTT (∼45 °C) with excellent antibacterial efficacy. This work presented here not only provides a facile approach to fabricate the MPDA@ZIF-8/PES nanosystem with the responsiveness of the bacterial infection environment, but also proposes a promising low-temperature PTT strategy to treat bacterial biofilm-infection effectively.

Intervention of Polydopamine Assembly and Adhesion on Nanoscale Interfaces: State-of-the-Art Designs and Biomedical Applications.

The translation of mussel-inspired wet adhesion to biomedical engineering fields have catalyzed the emergence of polydopamine (PDA)-based nanomaterials with privileged features and properties of conducting multiple interfacial interactions. Recent concerns and progress on the understanding of PDA's hierarchical structure and progressive assembly are inspiring approaches toward novel nanostructures with property and function advantages over simple nanoparticle architectures. Major breakthroughs in this field demonstrated the essential role of π-π stacking and π-cation interactions in the rational intervention of PDA self-assembly. In this review, the recently emerging concepts in the preparation and application of PDA nanomaterials, including 3D mesostructures, low-dimensional nanostructures, micelle/nanoemulsion based nanoclusters, as well as other multicomponent nanohybrids by the segregation and organization of PDA building blocks on nanoscale interfaces are outlined. The contribution of π-electron interactions on the interfacial loading/release of π electron-rich molecules (nucleic acids, drugs, photosensitizers) and the exogenous coupling of optical energy, as well as the impact of wet-adhesion interactions on the nano-bio interface interplay, are highlighted by discussing the structure-property relationships in their featured applications including fluorescent biosensing, gene therapy, drug delivery, phototherapy, combined therapy, etc. The limitations of current explorations, and future research directions are also discussed.

NIR-Actuated Remote Activation of Ferroptosis in Target Tumor Cells through a Photothermally Responsive Iron-Chelated Biopolymer Nanoplatform.

Ferroptosis is a new form of regulated cell death that shows promise for tumor treatment. Most current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies, and it would be of clinical significance to develop ferroptosis-inducing strategies with improved tumor specificity and modulability. Here we report a polydopamine-based nanoplatform (FeII PDA@LAP-PEG-cRGD) for the efficient loading of Fe2+ and ß-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. PDA nanostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe2+ ions. The NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis to facilitate bioreduction of the concurrently released ß-lapachone and enhance intracellular H2 O2 formation to promote the Fe2+ -mediated lipid peroxidation.

Implantable multifunctional black phosphorus nanoformulation-deposited biodegradable scaffold for combinational photothermal/ chemotherapy and wound healing.

Surgery is the mainstream treatment for melanoma, but its clinical implementation suffers from some major drawbacks including residual infiltrating melanoma cells at resection margins and severe tissue injury. In this study, a nanocomposite scaffold is developed for in-situ therapy after melanoma surgery as well as wound healing, which is fabricated by embedding photothermal-capable black phosphorus nanosheets (BPNSs) into bioresorbable Gelatin-PCL (GP) nanofibrous scaffold. GP scaffold is a clinically-tested biomaterial with temperature sensitivity and tissue-healing effect, while the BPNSs are loaded with the anticancer antibiotic of doxorubicin (DOX) and conjugated with NH2-PEG-FA for tumor-targeted delivery. The GP scaffold could undergo a sol-gel transition upon NIR irritation and release the BPNSs in situ. During this process, most of the BP-based nanoformulations were selectively internalized by the melanoma cells for the cooperative photothermal therapy and heat-triggerable DOX therapy, while some of the loaded DOX was released into the wound tissue to create a tumor-suppressive microenvironment. Moreover, BPNSs could be gradually degraded to phosphates/phosphonates and thus enhance tissue repair by activating the ERK1/2 and PI3K/Akt pathway. Meanwhile, the detached DOX molecules would also enter the wound tissues for continuous melanoma inhibition. Considering the anti-melanoma and wound healing effect of this composite scaffold, it may offer a facile strategy for the wound treatment after melanoma surgery.

Recent Progress in the Development of Multifunctional Nanoplatform for Precise Tumor Phototherapy.

Phototherapy, including photodynamic therapy and photothermal therapy, mainly relies on phototherapeutic agents (PAs) to produce heat or toxic reactive oxygen species (ROS) to kill tumors. It has attracted wide attention due to its merits of noninvasive properties and negligible drug resistance. However, the phototoxicity of conventional PAs is one of the main challenges for its potential clinical application. This is mainly caused by the uncontrolled distribution of PA in vivo, as well as the inevitable damage to healthy cells along the light path. Ensuring the generation of ROS or heat specific at tumor site is the key for precise tumor phototherapy. In this review, the progress of targeted delivery of PA and activatable phototherapy strategies based on nanocarriers for precise tumor therapy is summarized. The research progress of passive targeting, active targeting, and activatable targeting strategies in the delivery of PA is also described. Then, the switchable nanosystems for tumor precise phototherapy in response to tumor microenvironment, including pH, glutathione (GSH), protein, and nucleic acid, are highlighted. Finally, the challenges and opportunities of nanocarrier-based precise phototherapy are discussed for clinical application in the future.

A nanoplatform based on mesoporous silica-coated gold nanorods for cancer triplex therapy.

To enhance the efficacy of nanoparticle-based cancer therapy with reduced side effects and promote its clinical translation, a biocompatible nanocomposite based on mesoporous silica-coated gold nanorods (AuNR@MSN) for triple tumor therapy is reported in this study. The gold core served as a hyperthermia agent, while the MSN shell acted as a reservoir of chemotherapeutics owing to its excellent loading capacity. Cytochrome c with the apoptosis inducing function was anchored on the surface of AuNR@MSN to prevent drug leakage through redox-responsive disulfide bonds. The successful construction of a nanocomposite was confirmed by characterization of the physicochemical properties. In vitro and in vivo studies demonstrated that the nanocomposite displayed an optimizing anti-tumor effect with a synergistic strategy of excellent photothermal therapy, chemotherapy and protein therapy. Therefore, this cooperative strategy paves the way for high-efficiency oncotherapy with reduced side effects.

Near-Infrared Light-Triggered Nitric-Oxide-Enhanced Photodynamic Therapy and Low-Temperature Photothermal Therapy for Biofilm Elimination.

Photothermal treatment (PTT) involving a combination of therapeutic modalities recently emerged as an efficient alternative for combating biofilm. However, PTT-related local high temperature may destroy the surrounding healthy tissues. Herein, we present an all-in-one phototherapeutic nanoplatform consisting of l-arginine (l-Arg), indocyanine green (ICG), and mesoporous polydopamine (MPDA), namely, AI-MPDA, to eliminate the already-formed biofilm. The fabrication process included surface modification of MPDA with l-Arg and further adsorption of ICG via π-π stacking. Under near-infrared (NIR) exposure, AI-MPDA not only generated heat but also produced reactive oxygen species, causing a cascade catalysis of l-Arg to release nitric oxide (NO). Under NIR irradiation, biofilm elimination was attributed to the NO-enhanced photodynamic therapy and low-temperature PTT (≤45 °C). Notably, the NIR-triggered all-in-one strategy resulted in severe destruction of bacterial membranes. The phototherapeutic AI-MPDA also displayed good cytocompatibility. NIR-irradiated AI-MPDA nanoparticles not only prevented bacterial colonization but also realized a rapid recovery of infected wounds. More importantly, the all-in-one phototherapeutic platform displayed effective biofilm elimination with an efficiency of around 100% in a abscess formation model. Overall, this low-temperature phototherapeutic platform provides a reliable tool for combating already-formed biofilms in clinical applications.

A dual-functional implant with an enzyme-responsive effect for bacterial infection therapy and tissue regeneration.

Biomaterial-associated bacterial infection is one of the major causes of implant failure. The treatment of such an implant infection typically requires the elimination of bacteria and acceleration of tissue regeneration around implants simultaneously. To address this issue, an ideal implanted material should have the dual functions of bacterial infection therapy and tissue regeneration at the same time. Herein, an enzyme-responsive nanoplatform was fabricated in order to treat implant-associated bacterial infection and accelerate tissue regeneration in vivo. Firstly, Ag nanoparticles were pre-encapsulated in mesoporous silica nanoparticles (MSNs) by a one-pot method. Then, poly-l-glutamic acid (PG) and polyallylamine hydrochloride (PAH) were assembled by the layer-by-layer (LBL) assembly technique on MSN-Ag to form LBL@MSN-Ag nanoparticles. Furthermore, the LBL@MSN-Ag nanoparticles were deposited on the surface of polydopamine-modified Ti substrates. PG is a homogeneous polyamide composed of an amide linkage, which can be degraded by glutamyl endonuclease secreted by Staphylococcus aureus. Inductively coupled plasma spectroscopy (ICP) results proved that the LBL@MSN-Ag particles show a significant enzyme responsive release of Ag ions. Furthermore, results of antibacterial experiments in vitro showed that the Ti substrates modified with an LBL@MSN-Ag nanocoating presented an excellent antibacterial effect. As for an animal experiment in vivo, in a bacterium infected femur-defect rat model, the modified Ti implants effectively treated bacterial infection. More importantly, the results of micro-CT, haematoxylin-eosin staining and Masson's trichrome staining demonstrated that the modified Ti implants significantly promoted the formation of new bone tissue after implantation for 4 weeks. The present system paves the way for developing the next generation of implants with the functions of treating bacterial infection and promoting tissue regeneration.

Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy.

Biofilm formation is a main challenge in treatment of bone-implant-associated infections, resulting in tolerance to immune system and antibiotics. However, smart non-surgical or non-invasive treatment methods of combating established biofilm on an implant have been less reported. Herein, a therapeutic system consisting of mesoporous polydopamine nanoparticles (MPDA) to combat biofilm is reported for the first time. We develop a synergistic photothermal/photodynamic therapy (PTT/PDT) strategy aiming for biofilms eradication on titanium (Ti) implant, which is integrated with MPDA loading with photosensitizer Indocyanine Green (ICG) by π-π stacking. Specifically, MPDA is functionalized with RGD peptide to endow the modified Ti sample (Ti-M/I/RGD) with good cytocompatibility. More importantly, Ti-M/I/RGD implant remarkably kills Staphylococcus aureus (S. aureus) biofilm with an efficiency of 95.4% in vivo upon near infrared (NIR). After biofilm eradication, implant still displays great performance regarding osteogenesis and osseointegration. Overall, this study provides a PTT/PDT strtategy for the development of antibacterial Ti implants for potential orthpediac application.

Biocompatible MoS2/PDA-RGD coating on titanium implant with antibacterial property via intrinsic ROS-independent oxidative stress and NIR irradiation.

To inhibit bacterial infection in situ and improve osseointegration are essentially important for long-term survival of an orthopedic implant, in particular for infection-associating revision surgery. Herein, we fabricate a functional molybdenum disulfide (MoS2)/polydopamine (PDA)-arginine-glycine-aspartic acid (RGD) coating on titanium (Ti) implant to address above concerns simultaneously. The coating not only improved the osteogenesis of mesenchymal stem cells (MSCs), but also endowed Ti substrates with effective antibacterial ability when exposing to near-infrared (NIR) irradiation. It accelerated glutathione (GSH) oxidation via photothermal energy and induced intrinsic ROS-independent oxidative stress damage deriving from MoS2 nanosheets. The results displayed that RGD-decorated MoS2 nanosheets significantly increased the cellular osteogenic behaviors of MSCs via up-regulating osteogenesis-related genes (ALP, Runx2, Col I and OCN) in vitro. Moreover, the functionalized Ti substrates demonstrated great antibacterial efficiency of over 92.6% inhibition for S. aureus and E. coli under NIR-irradiation. Hyperthermia induced by photothermal effect accelerated the GSH consumption and ROS-independent oxidative stress destroyed the integrity of bacteria membranes, which synergistically led to protein leakage and ATP decrease. Furthermore, co-culture experiment showed that S. aureus contamination was efficiently cleaned from MoS2/PDA-RGD surface after NIR photothermal treatment, while MSCs adhered and proliferated on the MoS2/PDA-RGD surface. In an S. aureus infection model in vivo, MoS2/PDA-RGD modified Ti rods killed bacteria with an efficiency of 94.6% under NIR irradiation, without causing damage to normal tissue. More importantly, the MoS2/PDA-RGD modified Ti implants accelerated new bone formation in comparison with TNT implants in vivo.

Cascade-amplification of therapeutic efficacy: An emerging opportunity in cancer treatment.

Increasing research evidence reveals that cancer is complex disease involving many biological factors, processes and systems, which may severely limit the actual efficacy of conventional monotonic anticancer approaches. To overcome these obstacles in cancer treatment, a new strategy has been proposed by combining multiple synergistic therapeutic modalities accessing different but inherently related targets and acting sequentially. A major benefit of this strategy is that the multi-target mechanism could result in a cascade-amplification effect leading to enhanced anticancer activity. In this review, we provide a critical discussion on the application of cascade-amplification strategy in the treatment of various cancer indications, focusing on the rational combination of therapeutic agents and their mechanisms of action. A concise yet comprehensive analysis on the potential therapeutic benefit of this strategy was also included. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Hexagonal polypyrrole nanosheets from interface driven heterogeneous hybridization and self-assembly for photothermal cancer treatment.

Hexagonal polypyrrole (PPy) nanosheets with highly ordered lateral orientation were developed by the generation and directed self-assembly of dopamine induced FeOOH-PPy heterostructures on nanoscale THF/water interfaces. The size-controlled nanosheets possess attractive photothermal conversion properties, which facilitate efficient photothermal inhibition of cancer cells.

CaP coated mesoporous polydopamine nanoparticles with responsive membrane permeation ability for combined photothermal and siRNA therapy.

Combined photothermal and gene therapy provides a promising modality toward cancer treatment, yet facile integration and controlled codelivery of gene payloads and photothermal conversion agents (PTCAs) remains a great challenge. Inspired by the robust wet adhesion of marine mussels, we present a rationally designed nanosystem constructed by using hybrid mesoporous polydopamine nanoparticles (MPDA) with sub-100 nm sizes and a high photothermal conversion efficiency of 37%. The surface of the particles were modified with tertiary amines by the facile Michael addition/Schiff base reactions of PDA to realize high siRNA loading capacity (10 wt%). Moreover, a successful calcium phosphate (CaP) coating via biomineralization was constructed on the cationic nanoparticle to prohibit premature release of siRNA. The CaP coating underwent biodegradation in weakly-acidic subcellular conditions (lysosomes). The synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature the destabilization/disruption ability toward model cellular membranes via the greatly enhanced interfacial adhesion and interactions. Consequently, sufficient permeability of lysosomal membranes, and in turn, a high lysosomal escape efficiency, was realized, which then resulted in high gene silencing efficiencies via sufficient cytosolic delivery of siRNA. When an efficient knocking down (65%) of survivin (an inhibitor of apoptosis proteins) was combined with a subsequent photothermal ablation, remarkably higher therapeutic efficiencies were observed both in vitro and in vivo, as compared with monotherapy. The system may help to pave a new avenue on the utilization of bio-adhesive surfaces for handling the obstacles of combined photothermal and gene therapy. STATEMENT OF SIGNIFICANCE: Polydopamine (PDA) based porous photothermal-conversion agent (PTCA) with sufficiently high conversion efficiency was employed to deliver photothermal/gene therapy modalities towards cancer treatment. CaP coating via PDA-induced biomineralization was constructed to prohibit premature release of siRNA loaded in the pore space of the nanocarriers. Responsive degradation of CaP also led to the exposure of membrane-lytic surfaces built through the synergistic integration of tertiary amines and catechol moieties, and in turn the significantly enhanced lysosomal escape and cytosol siRNA delivery. Therapeutic targeting of survivin was successfully applied for activation of apoptosis and programmed cell death. Combined photothermal and gene therapy improved therapeutic effectiveness.

Copper-nanoparticle-embedded hydrogel for killing bacteria and promoting wound healing with photothermal therapy.

Bacterial infections at wound tissue sites usually delay the wound healing process and even result in severe life-threatening complications. Therefore, it is imperative to develop an efficient strategy to simultaneously enhance the antibacterial abilities and improve the wound healing process. Here, we report a composite hydrogel composed of methacrylate-modified gelatin (Gel-MA) and N,N-bis(acryloyl)cystamine (BACA)-chelated Cu nanoparticles (Cu NPs) via radical polymerization with a photoinitiator. The Cu NPs could effectively convert NIR laser irradiation (808 nm) energy into localized heat due to the localized surface plasmon resonance (LSPR) effect for effecting photothermal therapy. In vitro antimicrobial experiments revealed that the hybrid hydrogel exhibited predominant antibacterial efficacy against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria, while Cu-NP-embedded hydrogel + laser group exhibited superior antibacterial capacity. The excellent antibacterial properties can be attributed to the synergistic effect of photothermal performance and rapid release of copper ions (Cu2+) because of the laser irradiation of Cu NPs. Moreover, the released Cu2+ could stimulate NIH-3T3 fibroblast proliferation without any inflammatory responses. Moreover, chronic wound healing process of S. aureus-infected model was significantly accelerated with prominent antibacterial ability, reduced inflammatory response, and promoted angiogenesis ability in vivo. In summary, Cu-NP-embedded hydrogels are a promising candidate for skin tissue regeneration and potentially valuable for clinical applications.